Animal models of pancreatic ductal adenocarcinoma (PDAC) that faithfully mimic the human disease are necessary to allow researchers to develop effective early diagnosis, prevention, and treatment strategies. In recent years, several genetic mouse models of PDAC have been developed and have greatly improved our understanding of its biology. The genetic models in widespread usage today were developed by genetically altering either the embryonic pancreas or the adult cells that produce digestive enzymes, pancreatic acinar cells. That these models faithfully mimic the development of human PDAC is controversial because it is generally felt that in humans this disease develops within a different cell type, duct cells. Furthermore, PDAC is a disease of the elderly and is not found in children. Clearly, a genetic model based on genetical changes in adult pancreatic duct cells would provide an important model for investigation of this disease. Previous attempts to develop pancreatic duct-specific models relying on gene promoters that were duct specific but not pancreas specific (e.g. CK19) have failed because broad expression of oncogenes in all CK19-positive cells is embryonically lethal. In the proposed project, we will develop a mouse model in which gene expression is controlled specifically in adult pancreatic duct cells rather than any other cells. In order to do so, we have developed a novel strategy that uses a combination of two gene promoters that must be activated in tandem. For duct cell specificity, we will use the well-characterized CK19 promoter, which is active in duct cells throughout the body. For pancreatic specificity, we will use the PDX1 promoter, which is expressed in pancreatic precursor cells during embryonic development. We will assemble these promoters in a construct such that the duct cell- specific promoter CK19 is under the control of the pancreas-specific promoter PDX1. To control gene expression temporally, we will utilize our system to express a molecule that can be activated by a drug, tamoxifen. Once induced, this molecular is capable of activating or deleting genes in mice engineered specifically for this purpose, many of which are already available. This model will allow for the first time the specific regulation of pancreatic duct cell gene expression, which is useful for many physiological and pathological studies. Once the pancreatic duct-specific expression system is established, we will use it to activate an oncogene and inhibit a tumor suppressor to mimic the situation commonly found in humans to generate PDAC. Specimens of the PDAC that develops in this model will be compared with those from other genetic mouse models and with the human disease. We expect that this animal model of pancreatic cancer will be more clinically relevant and appropriate for translational research. PUBLIC HEALTH RELEVANCE: Success of this project will allow us to develop a pancreatic cancer mouse model in which cancer cells are derived from adult pancreatic duct cells instead of acinar cells or embryonic cells;such a model will thus more closely mimic the development of the disease in humans. We expect this model will be superior to others for investigations of pancreatic cancer diagnosis, prevention and treatment.